Crystalline fluoroquinolone arginine salt form

ABSTRACT

The invention relates to the new arginine salt forms of RS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, a process for their preparation and pharmaceutical formulations which comprise those arginine salt forms as the active ingredient for its use in treating microbial infections.

FIELD OF THE INVENTION

[0001] The present invention relates to a new crystalline form of afluoroquinolone, viz. arginine salt form thereof, a novel process formanufacturing the novel arginine salt form of the fluoroquinolone, theuse of the novel form of the arginine salt of the fluoroquinolone in themanufacture of pharmaceutical formulations and the use of the novel formof the arginine salt of the fluoroquinolone in medicine. Moreparticularly, it relates to the arginine salt form of the chiralfluoroquinoloneS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, a process for preparing the same and itsuse in pharmaceutical formulations and medicine.

BACKGROUND OF THE INVENTION

[0002] The chiral fluoroquinolone known under the nameS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid is described in JP Patent 63,192,753A, JPPatent 05,339,238A, and in our pending U.S. patent applications Ser.Nos. 09/566,875, 09/640,947 and 09/802,793 and WO 00/68229, PCTApplication Nos. PCT/IN00/0011 and PCT/IN01/00097.

[0003]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid is an optically active isomer of theracemic compound which is claimed in U.S. Pat. No. 4,399,134.

[0004]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid has an aqueous solubility of 0.8-2.0mg/ml over the pH range 8.0-9.5 at 28° C., thus creating problems inhaving to formulate the drug as a tablet or capsule, or in makingformulations for gavage and parenteral injection. The need for a salt isclearly indicated, as the lack of an appropriate salt form can hinderthe development of dosage forms acceptable for systemic use in mammals.

[0005]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid has a pKa value of 6.80 suggesting aweak acid character and thus an ability to form a salt with anappropriate base. Generally, conversion of a pharmacologically activecompound into a salt form induces a change in the compound'sphysicochemical properties such as solubility, absorption velocity, etc.

[0006] Pharmaceutically more desirable salt forms may be selected bystudying whether or not a crystalline or amorphous form, or polymorph orpseudopolymorph can be produced, and determining the propertiesincluding its physicochemical or biological properties. Apseudopolymorph is a polymorph that differs from a true polymorph by theincorporation of solvent (Solid-state Chemistry of Drugs, 2^(nd) Ed. S.R. Byrn et al (Eds). SSCI, Inc. 1999, p-514).

[0007] Pharmaceutically acceptable salts of racemic9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid such as salts with inorganic bases andorganic bases are mentioned in the text of Otsuka's U.S. Pat. No.4,399,134. Besides salts with inorganic bases and organic bases, aminoacid salts ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid are identified in our pending U.S. patentapplications Ser. No. 09/566,875 and U.S. patent application Ser. No.09/640,947, WO 00/68229 and PCT Application No. PCT/IN00/00111. Argininesalt forms ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid are identified in our pending U.S. patent application Ser. No.09/802,793 and PCT Application No. PCT/IN01/00097. The subject matter ofthese applications is incorporated herein by reference. To date, noliterature reference teaches about the amino acid salts ofRS-(+/−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid orR-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.

[0008]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, L-arginine salt 0.25 hydrate andS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt, 0.75 hydrate describedin Examples 7 and 8 of U.S. patent applications Ser. Nos. 09/566,875 and09/640,947, WO 00/68229 and PCT Application No. PCT/IN00/00111respectively are highly hygroscopic and turn into syrups on exposure ata relative humidity of 41%. Additionally, arginine salt forms describedin our pending U.S. patent application Ser. No. 09/802,793 and PCTApplication No. PCT/IN01/00097 are either amorphous or only partiallycrystalline and are to a certain degree hygroscopic. Many hydrates andsalts associated with water are susceptible to changes in humidity, arehygroscopic under adverse storage conditions and during pharmaceuticalprocessing of them to medicament forms.

[0009] The amino acid salts, inorganic base and alkali salts and organicbase salts and specially the arginine salt forms ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid were prepared and studied by theinventors and it was found that:

[0010] (a) an arginine salt may exist in a crystalline form havingdistinctive physicochemical, solubility and stability properties;

[0011] (b) the crystalline arginine salt is less prone than the sodiumsalt to absorb moisture at specified humidity levels;

[0012] (c) the crystalline arginine salt, possesses a lower propensityto cause phlebitis than the sodium and potassium salts as determined inrats by intravenous administration; and

[0013] (d) the crystalline arginine salt is less toxic in rodents thanthe alkali salt forms.

[0014] In summary, the crystalline form of the arginine salt ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid has been found by the inventors to havevery desirable properties in possessing under specified conditions, lesshygroscopicity, favourable aqueous solubility, a low propensity to causephlebitis, and favourable acute toxicity values. This form is expectedto be very useful as a pharmaceutical agent as compared with thepreviously described arginine salt forms, sodium salt, other inorganicbase/alkali salts, organic base salts and other amino acid salts. Theseadvantages will be apparent from the experimental data shown hereafter.

SUMMARY OF THE INVENTION

[0015] New arginine salts ofRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid andS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid are described. Compositions comprising one or more of these saltsand methods for preparing the salts are described. The use of the saltsin medicine is also described.

[0016] More particularly, a new L-arginine salt form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid of the formula I

[0017] is described in which x denotes 0, 0.25, 0.5, 0.75, 1.0, 2.0 or3.0. The novel crystalline form of the L-arginine salt ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid can be used in full scale manufacturing ofpharmaceutical formulations.

[0018] Antibacterial compositions comprising theS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt form as an active component are described.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The invention will now be described in further detail withreference to the accompanying drawings.

[0020]FIG. 1 represents the X-Ray Powder Diffraction (XRPD) spectrum ofthe crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt of the invention.

[0021]FIG. 2 represents the Differential Scanning Calorimeter (DSC)thermogram of the crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt of the invention.

[0022]FIG. 3 shows that the bulk density of the crystalline form of theinventionS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt is between 0.57 g/cm³ (untapped) and 0.64 g/cm³(tapped).

DISCLOSURE OF THE INVENTION

[0023] The main objective of the invention accordingly relates to new DLarginine salts and D-arginine salts and L-arginine salts of ofRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid andS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid.

[0024] Where particular stereoisomeric forms are described in thisinvention, they are meant to be substantially free of any otherstereoisomeric configuration. Substantially free should be taken to meanthat the active ingredient contains at least 90% by weight of thedesired stereoisomer and 10% by weight or less of other stereoisomers.Preferably the weight % ratio is better than 95:5 and most preferably99:1 or better. For example,S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine contains at least 90% by weightof this stereoisomer and 10% by weight or less of other configurationsof9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine.

[0025] The invention relates to new crystalline arginine salts ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, wherein the arginine component may beL-arginine, D-arginine or DL-arginine.

[0026] More particularly, the invention relates to a new crystallineL-arginine salt ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid of the formula I

[0027] in which x denotes 0, 0.25, 0.5, 0.75, 1.0, 2.0 or 3.0.Preferably, the L-arginine crystalline salt is a monohydrate.

[0028] The salt of Formula I has favourable aqueous solubility, isstable in humid conditions, has favorable bioavailability, has a lowerpropensity to cause phlebitis and lower toxicity when administered inmammals.

[0029] This invention also relates to a process for the preparation ofthe salt of Formula I, to its use in pharmaceutical compositions and inmedicine.

[0030] The arginine isomer used can be a racemic mixture of the chiralisomers or the R-isomer or the S-isomer. A preferred arginine isomer isthe S-isomer, that is L-arginine.

[0031] The arginine salt of the invention is described as crystallinebecause of the high degree of crystallinity of the form as depicted bythe XRD spectrum provided in FIG. 1. The form is shown to have distinctphysicochemical properties, is more stable to decomposition from uptakeof moisture at specified conditions, is distinguished by increasedstability, in particular during storage at specified humidities and canbe dried without caking or decomposing at elevated temperatures underreduced pressure. This form is particularly suitable for the preparationof stable pharmaceutical preparations, and has favourable biologicalproperties.

[0032] This form, while less hygroscopic than the compounds of Examples7 and 8 of U.S. patent applications Ser. Nos. 09/566,875 and 09/640,947,WO 00/68229 and PCT Application No. PCT/IN00/00111, is to a certaindegree hygroscopic. In stability studies at varying relative humidityconditions, this form was found to remain stable at relative humidityvalues of 22% at 25° C. In stability studies at elevated temperatures,this form remained stable with no decomposition up to 100° C., however,there was reduction in levels of water content and solvent content. Ondrying the forms at elevated temperatures up to 100° C. over differentperiods of time and under different humidity conditions, the amounts ofwater found associated with the salt are altered. However, there is nochange in the XRD-spectrum of the form. Without being bound to anytheory, from this the inventors infer that the amount of waterassociated with the preferred form of the invention is not superficialand the preferred form of the invention is substantially a monohydrate.

[0033] Hydrates are said to exist when the drug substance incorporateswater in the crystal lattice in either stochiometric ornon-stochiometric amounts” (Stephen Byrn, et. al., PharmaceuticalSolids: A strategic Approach to Regulatory Considerations, Pharma. Res.Vol. 12 (7), 1995, 945-954).

[0034] The inventors have found thatS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid arginine salt form of thisinvention, has acceptable aqueous solubility of 1 mg/ml extending to 30mg/ml, over the pH range 7.0-9.5 at ambient temperatures. The solubilityof this crystalline form is 30 mg/ml at pH 9.5. The L-arginine salt formis stable on heating at temperatures up to 100° C. at relative humidityranges up to 22%. This form has an acceptable dissolution rate.

[0035] The combination of physical properties of the novelS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt form of the presentinvention with respect to the degree of crystallinity, particlediameter, density, hygroscopicity, water content and content of othersolvents is favourable and permits the manufacturing ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt in a composition which possesses the desiredproperties.

[0036] The properties of this crystalline form including the meltingpoint is of a value that endow the form with desirable compression andflow properties for the processing of dosage forms useful for medicinalpurposes.

[0037] This crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt also has desirablephysicochemical properties as hereinbefore mentioned, and ischaracterised by parameters such as XRD, DSC, particle size and powderdensity.

[0038] The more crystalline form is described below:

[0039] (a) The degree of crystallinity as determined by X-ray powderdiffraction is shown in FIG. 1, X-ray powder diffraction (2θ):14.02±0.2, 14.82±0.2, 19.28±0.2, 22.12±0.2, 22.96±0.2, 23.46±0.2,28.36±0.2.

[0040] (b) A thermogram as determined by Differential ScanningCalorimetty has shown an exotherm at 194.93° C. (onset at 189.42° C.)and one endotherm at 251.26° C. as shown in FIG. 2. Other endotherms at87.83° C., 98.04° C., 144.03° C. and 159.14° C. are also observable,which endotherm readings may slightly fluctuate in different samples.

[0041] It is desirable that the crystalline form also has the followingproperties:

[0042] (c) Particle size measured as mean mass diameter (I) asdetermined by laser diffraction technique is less than or equal to 40μm, preferably the mean mass diameter is 32.00 μm±8 μm as determined bylaser diffraction technique, and as shown in Table 1;

[0043] (d) Density between 0.57 g/cm³ (untapped) and 0.64 g/cm³ (tapped)as shown in FIG. 3. Untapped density is defined as 25 gm/untappedvolume. The results are provided in FIG. 3. Tapped density is defined as25 gm/tapped volume. The results are provided in FIG. 3.

[0044] (e) Hygroscopicity not exceeding 3% increase of weight uponstorage for 14 days up to 22% relative atmospheric humidity at 30° C. asdetermined gravimetrically, but with full retention of flow properties;

[0045] (f) A content of water between 4.0% to 4.4% by weight asdetermined by titration according to Karl Fischer.

[0046] (g) The content of the organic solvent is less than 0.05% byweight as determined by gas chromatography. When acetone is used assolvent in the preparation of this form, the content of acetone is lessthan 0.3%, preferably less than 0.2% by weight as determined by gaschromatography. When acetonitrile is used as solvent in the preparationof this form, the content of acetonitrile is less than 0.04%, preferablyless than 0.03% by weight as determined by gas chromatography.

[0047] (h) The solubility in a solution of pH 9.5 is 30.0 mg/ml.

[0048] TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt of this inventionexhibits the same antibacterial minimum inhibitory concentration (MIC)values as the free active ingredient,S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid.

[0049] The crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid L-arginine salt has antimicrobialactivity:

[0050] It has potent activity against resistant Staphylococcus aureus.

[0051] It has ability to resist drug efflux in Gram-positive organisms.

[0052] It has the unusual ability to retain potency at an acidic pH of5.5.

[0053] It is effective in treating respiratory pathogens.

[0054] It is effective in treating resistant mutants.

[0055] It has superior cidal action against slow-growing Staphylococci.

[0056] It scores over the standard drugs in terms of eradicationefficacy for Staphylococci from vital organs and thigh muscle.

[0057] It exhibits unusual superior cidal effect even with a highdensity bacterial inoculum (10⁸ cfu/ml); a standard recommended inoculumis 10⁶ cfu/ml.

[0058]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid D-arginine salt,S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid DL-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid L-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid D-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid DL-arginine salt,R,S-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid L-arginine salt,R,S-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid D-arginine salt andR,S-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid DL-arginine salt also haveantimicrobial activity. It is to be noted that asS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid has more potent antimicrobialactivity thanR-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid andRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid, this same difference in potencywill also be displayed by their respective arginine salts.

[0059] The present invention also relates to a process for preparing thenovel crystalline form of the arginine salt. A process for themanufacture of the crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt comprises the followingconsecutive steps:

[0060] a) dissolvingS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid with L-arginine in an organic solvent and water to form a solution;

[0061] b) cooling the solution to provide a crystalline substance;

[0062] c) isolating the crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt at <35° C. by filtration or centrifugation;

[0063] d) purifyng and drying the crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid L-arginine salt using conventionalmethods.

[0064] The ratio of L-arginine toS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H,benzo [ij] quinolizine-2-carboxylic acid ranges from 0.93 to 1.49 molarequivalent of L-arginine to 1.0 molar equivalent ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H,benzo [i,j] quinolizine-2-carboxylic acid. Preferably the molar ratio ofL-arginine toS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H,benzo [i,j] quinolizine-2-carboxylic acid is 1.0:1.0 mole.

[0065] Preferably the solvents used in step (a) are an organic solventand water; more preferably the organic solvent is acetone oracetonitrile. The proportion of organic solvent to water ranges from 20%to 80% depending upon the organic solvent used. The proportion of waterto organic solvent ranges from 16.6% water to 33.3% water of the totalvolume of organic solvent and water used. A preferred proportion ofwater to organic solvent is 20% water of the total volume of water andorganic solvent used.

[0066] Preferably the solution of step (a) is stirred at a temperature50 to 60° C. for 45-60 minutes.

[0067] Preferably in step (a) the solution is treated with activatedcharcoal at 50 to 60° C., filtered hot and diluted with an additionalamount of organic solvent. In the case when the organic solvent isacetone, the ratio ranges from 0.9 to 1.1 parts by weight of the acid to2.4 to 2.6 parts by volume of water to 9.0 to 11 parts by volume ofacetone, preferably 1 part by weight of acid to 2.5 parts by volume ofwater to 10 parts by volume of acetone. In the case when the organicsolvent is acetonitrile, the ratio ranges from 0.9 to 1.1 parts byweight of the acid to 2.3 to 2.5 parts by volume of water to 11.0 to 13parts by volume of acetonitrile, preferably 1 part by weight of acid:2.4parts by volume of water:12 parts by volume of acetonitrile.

[0068] The amount of water used depends on the nature of the organicsolvent used. When the organic solvent is acetone, the preferred ratioof water to acetone is 1 part by volume of water to 4 parts by volume ofacetone and when acetonitrile is the organic solvent used, the preferredratio of water to acetonitrile is 1 part by volume of water and 5 partsby volume of acetonitrile. It is also based on the amount ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H,benzo [i,j] quinolizine-2-carboxylic acid and the nature of the organicsolvent used, preferably when 1 part by weight of acid is used, 2.5parts by volume of water are used and 5 parts to 10 parts by volume ofacetone are used. When acetonitrile is the solvent, preferably for 1part by weight of acid, 2.4 parts by volume of water and 12 parts byvolume of acetonitrile are used.

[0069] In step (b), the solution is cooled from 0° C. to 40° C., morepreferably from 30° C. to 35° C.

[0070] Preferably in step (c), a crystalline substance is obtained byfiltration.

[0071] In a preferred embodiment, L-arginine is added to a suspension orsolution ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid in an organic solvent and water. Theorganic solvent may be selected from acetone or acetonitrile. Theamounts of organic solvent and water used are so manipulated that whenthe reaction mixture is stirred for 45-60 minutes at 50 to 60° C. asolution is provided, and subsequent cooling from 0° C. to 40° C.,preferably to 30-35° C. provides the crystalline salt of the invention.The desired salt is isolated by filtration or centrifugation and washedwith additional amount of the respective organic solvent used and driedpreferably under reduced pressure and heating up to 65-70° C.

[0072] Yet a further aspect of the invention is that the synthesis ofoptically pureS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt is also preferably preparedby enhancement of the optically impure or partially pureS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid using L-arginine, followed bycrystallisation of the resulting optically pure salt. A less opticallypureS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid used in this process may range from amixture of 70% of S-(−)-isomer and 30% of R-(+)-isomer to 97% ofS-(−)-isomer and 3% of R-(+)-isomer, preferably a mixture of 88% ofS-(−)-isomer and 12% of R-(+)-isomer.

[0073] A general method for enhancement in optically purity ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid using L-arginine comprises,

[0074] (a) suspending a partially optically impure mixture of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid comprising 70% S-(−) isomer and 30%R-(+)- isomer to 97% S-(−) isomer and 3% R-(+)-isomer, preferably 88%S-(−) isomer and 12% R-(+)-isomer in water and organic solvent mixture.The ratio of water to organic solvent can be selected from 1.0:1.0 to1.0:2.0, preferably 1.0:1.18. Organic solvent can be selected fromacetone or acetonitrile, preferably acetone. An equimolar quantity ofL-arginine is added to the suspension and the suspension is heated at 40to 70° C., preferably 50 to 60° C. to obtain a clear solution. 2 to 3times more amount of the organic solvent than originally used is added,preferably 2.4 to 2.5 times more, and the suspension is stirred at 0 to45° C., preferably 30 to 35° C. for 1 hr to 5 h, preferably 2 hr, toeffect the crystallization. The product is isolated by filtration anddrying.

[0075] Yet a further aspect of the invention is that the synthesis ofoptically pureS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt is also preferably preparedby enhancement of the optically impure or partially pureS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid using D-arginine, followed bycrystallisation of the resulting optically pure salt. A less opticallypureS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid used in this process may range from amixture of 70% of S-(−)-isomer and 30% of R-(+)-isomer to 97% ofS-(−)-isomer and 3% of R-(+)-isomer, preferably a mixture of 88% ofS-(−)-isomer and 12% of R-(+)-isomer.

[0076] The process for manufacturing the crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt differs from theearlier known processes in that it can be controlled to give acrystalline polymorphic form of the salt form through use of therespective conditions that are described and shown to provide theresult. This process can be carried out in conventional chemical processequipment. Preferably the product that is produced is substantially amonohydrate.

[0077] Another aspect of the invention is the preparation of the DL- andD-arginine salt ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid and of the DL-, D- and L-arginine salts ofR(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid and DL-, D- and L-arginine salt ofRS(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid

[0078] The process comprises using a suspension of the appropriateenantiomer/racemic mixture of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid in a C₁-C₃ alkanol solvent, preferably methanol, ethanol,isopropanol, adding an aqueous solution of the appropriate enantiomer ofarginine in preferably equimolar quantities, stirring the mixture at40-70° C., preferably 60-65° C. for 10-45 minutes, preferably 15minutes, evaporating the solution to dryness under reduced pressure togive the desired salt.

[0079]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid may be prepared by following the proceduredescribed in U.S. Pat. No. 4,399,134. L-arginine salt and D-arginine arecommercially available from Ajinomoto, Japan. The cost of naturallyoccurring L-arginine is considerably cheaper than the enantiomericD-arginine. One facet of this invention is the description ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine which utilizes the inexpensivenaturally occurring and readily available L-arginine for making thecrystalline salt of the invention.

[0080] A comparison between the novel form of the L-arginine saltprepared by the process of the present invention and those obtained fromthe experiments disclosed in the prior art shows that the salt of thepresent invention is substantially a monohydrate, is stable up to 100°C., and at relative humidity up to 22% at 25° C., and has favorableaqueous solubility, all attributes essential to the preparation ofpharmaceutical compositions. This novel crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt is stable under typical storage conditions, hasgood bioavailability in mammals, has lower phlebitis-forming potentialon administration to mammals, has low or reduced toxicity, hasacceptable disintegration and dissolution rates, and hence is veryuseful for pharmaceutical manufacturing and for use in medicine. Theform is specially suitable for treating diseases caused by microbialinfections. The form is suitable for long-term intravenous therapy incritically ill patients or patients in intensive care units. Injectablepreparations of the L-arginine salt can be readily prepared in view ofits availability in a bulk form that remains stable under specifiedconditions, its favorable aqueous solubility, its ideal suitability innot causing venous inflammation on repeated intravenous administration,and its safety from adverse toxicity.

[0081]S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt form of thisinvention can be present in pharmaceutical formulations as the onlyactive compound or can be combined with other active ingredients such asother antibacterial agents.

[0082] The invention therefore also relates to liquid and solidpharmaceutical formulations which comprise the arginine salt of theinvention, such as for example, injectable solutions, suspensions,emulsions, tablets, coated tablets, coated tablet cores, capsules,solutions, troches, dispersions, patches, powders, lotions, gels,sprays, pellets, granules, suppositories, hard or soft gelatin capsules,ointments, creams and the like.

[0083] The pharmaceutical formulations are prepared in a manner knownper se, for example by mixing, stirring, suspending, dispersing,emulsifying, dissolving and the like, the active compounds with or inthe pharmaceutical auxiliaries such as a carrier, diluent, solvent orexcipient and processing the components to pharmaceutically suitableforms for parenteral, oral, topical, intranasal, buccal or rectaladministration and the like.

[0084] Pharmaceutical formulations can be formulated together withauxiliaries and additives usually employed in pharmacy, such as tabletbinders, fillers, preservatives, tablet disintegrating agents, flowregulating, agents, plasticizers, wetting agents, dispersing agents,emulsifiers, solvents, pH altering additives, flavourings and the like.

[0085] The total daily dose range is generally from about 200 mg toabout 1500 mg of the arginine salt form. However, the dose may be higheror lower depending on the needs and conditions of the patient.

[0086] The following detailed examples serve to more fully illustratethe invention without limiting its scope.

EXAMPLE 1 Preparation ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt Hydrate

[0087]S-(−)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid (750 gm, 2.083 mole) was suspended in acetone (2250 ml). To thissuspension was added L-arginine (337.5 g, 1.939 mole) and water (1875ml) under stirring. The mixture was stirred at 55 to 60° C. for one hourto obtain a clear solution. To the solution was added activated carbon(37.5 gm) and the solution was filtered hot. To the filtrate was addedacetone (5250 ml). The reaction mixture was stirred for an additionalfor 2 hours at 30-35° C. then allowed to cool to 5° C. The obtainedsolid was filtered at suction and washed with acetone. The wet solid wasdried in a vacuum oven at 80-85° C. to afford titled compound as a creamcoloured powder. Yield 1035 gm. melting point 238-243° C. [α]_(D)²⁵=−184.25° (c=1, methanol).

EXAMPLE 2 Preparation ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt Hydrate

[0088] To a three-necked round bottom flask fitted on oil bath andequipped with magnetic stirrer and reflux condenser;S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid (2 gm, 5.55 mmoles) and L-arginine (1.44 gin, 8.27 mmole) werecharged in a mixture of acetone (10 ml) and water (5 ml). The reactionmixture was slowly heated under stirring at 50 to 60° C. temperature toobtain a clear solution. The solution was allowed to cool to 30-35° C.and then was further cooled in ice bath. The solid separated wasfiltered at suction and was washed with a cold mixture of acetone (10ml) and water (5 ml). The crystalline solid was dried in a vacuum ovenat 65-70° C. to afford 2.4 gm (81%) dry compound, [∝]_(D) ²⁵ valuecalculated on anhydrous basis is 183° (c=1, methanol).

EXAMPLE 3 Preparation ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt Hydrate

[0089] To the suspension ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid (100 gm, 0.278 mole) in acetone (300 ml) was added L-arginine (45gm, 0.258 mole) and water (250 ml). The mixture was heated to 50 to 60°C. temperature for one hour to obtain a clear solution. Activatedcharcoal (5 gm) was added to the solution and the solution was filteredhot. To the filtrate was added acetone (700 ml) and the mixture wascooled gradually to 30 to 35° C. temperature, a solid crystallized outwhich was filtered and washed with aqueous acetone and finally withacetone. On drying in vacuum oven at 65 to 70° C.S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt was obtained as acrystalline powder weighing 137 gm (92%). [∝]_(D) ²⁵ value calculated onanhydrous basis is −183.34° (c=1, methanol)

EXAMPLE 4 Preparation ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt Hydrate

[0090] To a three necked 1 lit. round bottom flask fitted on the waterbath and equipped with mechanical stirrer, thermometer pocket and refluxcondenser was chargedS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (25 gm, 69.44 mmole) and acetonitrile (75ml). Stirring was started and to the stirred suspension was chargedpowdered L-arginine (12.16 gm, 69.88 mmole) followed by distilled water(60 ml). The reaction mixture was stirred at the temperature between 50to 60° C. for one hour to obtain a homogeneous clear solution. Clearreaction mixture was then charged 225 ml fresh acetonitrile understirring. Activated charcoal (3 gm) was added to the solution and thesolution was filtered hot. Filtrate was allowed to cool to 30 to 35° C.under stirring. The reaction mixture was stirred for additional 3 hoursat this temperature. The crystalline solid was filtered at suction andthe wet cake was washed with 25 ml acetonitrile. Resulting crystallinesolid was dried under vacuum at 65 to 70° C. to furnish 34.5 gm (93%)title compound, [∝]_(D) ²⁵ value calculated on anhydrous basis is−183.99° (c=1, methanol).

EXAMPLE 4-A Preparation ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt

[0091] A mixture of the two enantiomers [88.24% S-(−)-isomer and 11.76%R-(+)-isomer] of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (1.5 gm, 4.16 mmol) was suspended in amixture of acetone (4.5 ml) and water (3.8 ml). To the stirredsuspension L-arginine (0.725 gm, 4.16 mmol) was added. The mixture waswarmed to a temperature between 50-60° C. to obtain a clear solution.Acetone (11 ml) was added to the solution, which was then cooled to30-35° C. and stirred for 2 hours. The crystalline solid obtained wasfiltered under suction and the residue was washed with 2 ml acetone. Theresulting solid was dried to furnish 1.8 gin (92%) of the titlecompound.

[0092] Chiral analysis of the crystals were performed by chromatographyon an analytical chiral column. The optical purity of the crystals wasfound to be 97.06%. The cystallinity was determined by powder X-raydiffraction.

EXAMPLE 4-B

[0093] The above experiment was repeated on the mixture of enantiomerhaving optical purity 89% S-(−)-isomer and 11% R-(+)-isomer of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo1H,5H-benzo[i,j] quinolizine-2-carboxylic acid using acetonitrileinstead of acetone in accordance with the conditions and quantitiesdescribed in Example 4-A to provide the product of which optical puritywas enhanced to 98% as shown by chiral chromatography.

EXAMPLE 5 Preparation ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid D-arginine Salt

[0094] To a suspension ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid (1 g, 2.77 mmol) in methanol (50 ml) was charged a solution ofD-arginine (0.483 g, 2.77 mmol) in 10 ml water at 60-65° C. The clearsolution obtained was stirred for 15 minutes at 60-65° C. The reactionmixture was evaporated to dryness under reduced pressure to give 1.3 g(88%) of the title compound, m.p. 241-243° C., [∝]_(D) ²⁵=−174.4° (c=1,methanol).

EXAMPLE 6 Preparation ofR-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt

[0095] This compound may be prepared according to the proceduredescribed in Example 5 usingR-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid instead ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid and L-arginine instead of D-arginine.

EXAMPLE 7 Preparation ofR-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid D-arginine Salt

[0096] This compound may be prepared following Example 6 by substitutingan equivalent amount of D-arginine for L-arginine. m.p. (DSC) 232.0° C.,[∝]_(D) ²⁵=+171.4° (c=1, methanol)

EXAMPLE 8 Preparation ofRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid L-arginine Salt

[0097] This compound may be prepared following Example 6 by substitutingRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid forR-(+)-9-fluoro-6,7-dihydro-8-(4-bydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid.

EXAMPLE 9 Preparation ofRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicAcid D-arginine Salt

[0098] This compound may be prepared following Example 8 by substitutingan equivalent amount of D-arginine for L-arginine. M.p (DSC) 234.8° C.

[0099] The crystallineS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt prepared according to Examples 1-4B possesses thefollowing properties:

[0100] a) Crystalline form, with a degree of crystallinity as determinedby X-ray powder diffraction and as shown in FIG. 1.

[0101] b) A thermogram as determined by Differential scanningcalorimetry and as shown in FIG. 2.

[0102] c) Particle size measured as mean mass diameter (MMD) of lessthan or equal to 40 μm, as determined by laser diffraction technique.

[0103] d) Bulk density of 0.57 g/cm³ (untapped) and 0.64 g/cm³ (tapped)as shown in FIG. 3. Untapped density is defined as 25 gm/untappedvolume. The results are provided in FIG. 3. Tapped density is defined as25 gm/tapped volume. The results are provided in FIG. 3.

[0104] e) Hygroscopicity of 3% increase of weight upon storage for 14days up to 22% relative atmospheric humidity at 30° C. as determinedgravimetrically.

[0105] f) Water content of between 4.0% to 4.4% by weight as determinedby titration according to Karl Fischer.

[0106] g) A content of acetone of 0.011% by weight, or of acetonitrileof 0.03% by weight, as determined by gas chromatography.

TEST EXAMPLE 1 X-ray Diffraction Analysis

[0107] 300 mg each ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[I,j]quinolizine-2-carboxylic acid L-arginine salt prepared as inExample 1 was thinly spread on a sample holder. X-ray diffractionanalyses (40 kv×40 mA Rigaku D/max 2200) were performed under theconditions listed below:

[0108] Scan speed 5°/min

[0109] Sampling time 7 min

[0110] Scan mode: continuous

[0111] 2θ/θ reflection

[0112] Cu target (Ni filter)

[0113] Results of the X-ray diffraction analysis on the crystalline formis depicted in FIG. 1.

TEST EXAMPLE 2 Thermal Analysis of theS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl-5-methyl-1-oxo-1H,5H-benzo[I,j]quinolizine-2-carboxylic Acid L-arginine Salt

[0114] For the Differential Scanning Calorimetry, METTLER TOLEDO STARsystem was used. 5 to 6 mg of the sample was weighed into the aluminumpan, which was then press sealed with an aluminium lid. After three tinyneedle holes were made on the lid the sample was tested by heating from(30° C.) to (300° C.) at a rate of 10° C./min. Result can be seen fromFIG. 2. There is an exothermic peak at around 194.93° C. and anendothermic peak at 251.26° C., other endothermic peaks are observableat 87.83° C., 98.04° C., 144.03° C. and 159.14° C.

TEST EXAMPLE 3 Bulk Density Determination

[0115] For untapped and tapped density determination Bulk DensityApparatus (R.V. Electronics, Mumbai) was used. 25 g of the sample wasslowly poured into a dry clean stoppered measuring cylinder and filledvolume was measured to obtain untapped density.

[0116] Untapped density=25 g/untapped volume.

[0117] Then the measuring cylinder was fixed to Bulk Density Apparatusand sample was tapped (150 times) and volume was measured to furnish thetapped volume.

[0118] Tapped density=25 g/Tapped volume.

[0119] The results are shown in FIG. 3.

TEST EXAMPLE 4 Mean Mass Diameter Determination

[0120] For mean mass diameter Master Sizer of Malvern Instrument LTDU.K. was used under the conditions listed below:

[0121] Lens/Focus: 300 mm

[0122] Solvent: Hexane

[0123] Analysis model: Polydisperse

[0124] Obstruction value: 20-23%

[0125] The particle size measured as mean mass diameter of thecrystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt of the invention from fourdifferent samples made by the procedure described in example 1 is asgiven in Table 1. TABLE 1 Sample No. Mean mass diameter (μm) 1 32.92 224.22 3 34.51 4 39.07

[0126] The mean value is 32.68 μm.

1. A compound which is selected from the DL-, D- or L-arginine salts ofracemic or optically active isomers of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.
 2. A compound according to claim 1,which is selected from the DL-, D- or L-arginine salts of opticallyactive isomers of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, which selected compound issubstantially free of any other9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid-arginine salt stereoisomer.
 3. Acompound of claim 2, which is selected fromS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt andS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid D-arginine salt.
 4. A compound ofclaim 2, wherein the weight ratio ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt orS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt to other stereoisomers of this salt is at least95:5.
 5. A compound of claim 4, wherein the weight ratio ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt orS(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt to other stereoisomers of this salt is at least99:1. 6.S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt of the formula I

in which x denotes 0, 0.25, 0.5, 0.75, 1.0, 2.0 or 3.0 in a crystallineform.
 7. AS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 6,wherein x=1.
 8. AS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt having the followingX-ray powder diffraction data: (2θ): 14.02±0.2, 14.82±0.2, 19.28±0.2,22.12±0.2, 22.96±0.2, 23.46±0.2, 28.36±0.2.
 9. AS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt having the followingX-ray powder diffraction data: (2θ): 14.02±0.2, 14.82±0.2, 19.28±0.2,22.12±0.2, 22.96±0.2, 23.46±0.2, 28.36±0.2; a DSC exotherm at 194.93° C.(onset at 189.42° C.) and one endotherm at 251.26° C. and a watercontent of between 4.0 and 4.4% by weight as determined by titrationaccording to Karl Fischer.
 10. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 8,having an DSC exotherm at 194.93° C. (onset at 189.42° C.) and oneendotherm at 251.26° C.
 11. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 8, wherein the solubility in asolution of pH 9.5 is 30.0 mg/ml.
 12. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 9,wherein the solubility in a solution of pH 9.5 is 30.0 mg/ml.
 13. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 8,wherein the mean mass diameter as determined by laser diffractiontechnique is less than or equal to 40 μm.
 14. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim13, wherein the diameter is less than 32 μm.
 15. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 8, wherein the density isbetween 0.57 g/cm³ (untapped) and 0.64 g/cm³ (tapped).
 16. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 9, wherein the density isbetween 0.57 g/cm³ (untapped) and 0.64 g/cm³ (tapped).
 17. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 6, wherein the water content isbetween 4.0% and 4.4% by weight as determined by titration according toKarl Fischer.
 18. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 8,wherein the water content is between 4.0 and 4.4% by weight asdetermined by titration according to Karl Fischer.
 19. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 8,having an organic solvent content less than 0.05% by weight asdetermined by gas chromatography.
 20. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 9,having an organic solvent content less than 0.05% by weight asdetermined by gas chromatography.
 21. TheS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt according to claim 6,wherein the hygroscopicity is less than 3% increase of weight uponstorage for 14 days at up to 22% relative atmospheric humidity asdetermined by gravimetrically. 22.S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid D-arginine salt having m.p. 241-243°C., and [∝]_(D) ²⁵=−174.4° (c=1, methanol). 23.R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt. 24.R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid D-arginine salt having m.p. (DSC)232.0° C., and [∝]_(D) ²⁵=+171.4° (c=1, methanol) 25.R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid DL-arginine salt.
 26. A compoundselected fromRS-(±)-9-fluoro-6,7-dihydro-8-(4-bydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid DL-arginine salt,RS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt orRS-(±)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid D-arginine salt.
 27. A process forthe manufacture ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt comprising the steps of: a) dissolvingS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid with L-arginine in an organic solvent and water to form a solution;b) cooling the solution to provide a crystalline substance; c) isolatingthe crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-bydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt at <35° C. by filtration or centrifugation; and d)purifying and drying the crystalline form ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt.
 28. The according toclaim 27, wherein the molar ratio ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid to L-arginine is in the range from1.0:0.93 to 1.49.
 29. The process according to claim 27, wherein themolar ratio ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid to L-arginine is 1:1.
 30. The processaccording to claim 27, wherein the organic solvent is selected fromacetone or acetonitrile.
 31. The process according to claim 27, whereinthe percentage of water in the solvent mixture is 20%-80%.
 32. Theprocess according to claim 27, wherein the solution of step a) isstirred at 50 to 60° C.
 33. A method for enhancing optical purity ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt comprising, (a) suspendinga partially optically impure mixture of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid comprising 70% S-(−) isomer and 30%R-(+)-isomer to 97% S-(−) isomer and 3% R-(+)-isomer in water andorganic solvent to form a suspension, b) adding an equimolar quantity ofL-arginine to the suspension and heating suspension at 40 to 70° C. toobtain a clear solution, and c) adding 2 to 3 times more of the organicsolvent added in step a) and stirring at 0 to 45° C., for 1 hr to 5 hr,to effect the crystallization and isolating the product by filtrationand drying.
 34. A composition comprisingS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 6 and a carrier, diluent,solvent or excipient.
 35. A composition comprisingS-(−)-9-fluoro-6,7-dihydro-8-(4-bydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 7 and a carrier, diluent,solvent or excipient.
 36. A composition comprisingS-(−)-9-fluoro-6,7-dihydro-8-(4-bydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 8 and a carrier, diluent,solvent or excipient.
 37. A composition comprisingS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 9 and a carrier, diluent,solvent or excipient.
 38. A composition comprising a compound selectedfrom the group consisting ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt,S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt,RS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt,RS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt andRS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt and a carrier, diluent, solvent or excipient. 39.A method for treating a disease caused by a microbial infection in amammal comprising administering an effective amount ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 6 to the mammal in need thereof.40. A method for treating a disease caused by a microbial infection in amammal comprising administering an effective amount ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 7, to the mammal in needthereof.
 41. A method for treating a disease caused by a microbialinfection in a mammal comprising administering an effective amount ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 8, to the mammal in needthereof.
 42. A method for treating a disease caused by a microbialinfection in a mammal comprising administering an effective amount ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt according to claim 9, to the mammal in needthereof.
 43. A method for treating a disease caused by a microbialinfection in a mammal comprising administering an effective amount of acompound selected of the group consisting ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt,S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt,RS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt,RS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt andRS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt to the mammal in need thereof.
 44. A process forthe manufacture of a compound selected from the group selected from thegroup consisting ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt,S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt,R-(+)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine salt,RS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid L-arginine salt,RS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid D-arginine salt andRS-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylicacid DL-arginine saltS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-oxo-1H,5H-benzo[i,j]quinolizine-carboxylicacid D-arginine salt comprising the steps of: a) suspending anentaniomer or racemic mixture of9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-oxo-1H,5H-benzo[i,j]quinolizine-carboxylicacid in a C₁-C₃ alkanol solvent and adding an aqueous solution of DL, Lor D arginine; b) stirring the mixture at 40-70° C. for 10-45 minutes;and evaporating the solution to dryness under reduced pressure.
 45. Aprocess according to claim 44, wherein the amounts used ofS-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-oxo-1H,5H-benzo[i,j]quinolizine-carboxylicacid and D-arginine are equal molar amounts.
 46. A process according toclaim 44, wherein the solvent is selected from methanol, ethanol, orisopropanol.